WO2006091770A2 - Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof - Google Patents
Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof Download PDFInfo
- Publication number
- WO2006091770A2 WO2006091770A2 PCT/US2006/006519 US2006006519W WO2006091770A2 WO 2006091770 A2 WO2006091770 A2 WO 2006091770A2 US 2006006519 W US2006006519 W US 2006006519W WO 2006091770 A2 WO2006091770 A2 WO 2006091770A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- hplc
- ether
- area
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 75
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title claims abstract description 35
- 229960000672 rosuvastatin Drugs 0.000 title claims abstract description 35
- 150000003839 salts Chemical class 0.000 title claims description 21
- -1 rosuvastatin alkylether Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 189
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 135
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 71
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 45
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 44
- 239000003480 eluent Substances 0.000 claims description 35
- 239000011541 reaction mixture Substances 0.000 claims description 34
- 125000006239 protecting group Chemical group 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 230000014759 maintenance of location Effects 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 150000001768 cations Chemical class 0.000 claims description 10
- 150000004702 methyl esters Chemical group 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 238000005259 measurement Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 235000019439 ethyl acetate Nutrition 0.000 claims description 8
- 239000003550 marker Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 229940093499 ethyl acetate Drugs 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 238000003818 flash chromatography Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000010899 nucleation Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 33
- 239000000543 intermediate Substances 0.000 abstract description 10
- 150000005215 alkyl ethers Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 40
- 239000008186 active pharmaceutical agent Substances 0.000 description 20
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 17
- 229960004796 rosuvastatin calcium Drugs 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 0 CC(C)c1nc(N(C)*)nc(-c(cc2)ccc2F)c1C=CC(CCC*)=O Chemical compound CC(C)c1nc(N(C)*)nc(-c(cc2)ccc2F)c1C=CC(CCC*)=O 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940066901 crestor Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000006241 alcohol protecting group Chemical group 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010954 commercial manufacturing process Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1896—Compounds having one or more Si-O-acyl linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to rosuvastatin and salts and intermediates thereof having a low level of alkylether impurity and processes for the preparation thereof.
- Rosuvastatin calcium has the chemical name (7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy- (E)-6-heptenoic acid-calcium salt), and has the following chemical formula:
- Rosuvastatin calcium Rosuvastatin calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium is a superstatin, which can lower LDL-cholesterol and triglycerides more effectively than first generation statin drugs.
- Rosuvastatin calcium is marketed under the name CRESTOR for the treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5 mg to about 40 mg.
- hydrofluoric acid is performed by using a solution of hydrofluoric acid.
- hydrofluoric acid is problematic on an industrial scale because of the strong corrosive properties and very toxic vapors; contact with glass or metal should also be avoided.
- Rosuvastatin calcium can contain extraneous compounds or impurities originating from various sources. These impurities in rosuvastatin calcium, or any active pharmaceutical ingredient (API), are undesirable and, in extreme cases, may even be harmful to a patient being treated with a dosage form containing the API.
- API active pharmaceutical ingredient
- Impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and from the manufacturing process, including the chemical synthesis of the API.
- Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products of the reaction, and degradation products.
- the stability of an API during storage is a critical factor in the shelf life of the API, and so affects the ability to commercialize an API.
- the purity of the API resulting from the manufacturing process also affects the ability to commercialize an API. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent.
- the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
- the API is analyzed by HPLC or TLC analysis to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
- the API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and thus, is as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
- side products, by-products, and adjunct reagents are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate.
- impurities such as that in a chromatogram, or a spot on a TLC plate.
- the impurity can be identified, e.g., by its relative position on the TLC plate (wherein the position on the plate is measured in cm from the base line of the plate) or by its relative position in the chromatogram of the HPLC (where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector).
- the relative position in the chromatogram is known as the "retention time.”
- the retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors.
- practitioners use the "relative retention time" ("RRT") to identify impurities. (Strobel p. 922).
- RRT relative retention time
- the RRT of an impurity is its retention time divided by the retention time of a reference marker or reference standard. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker or reference standard for determination of the RRT.
- impurity rosuvastatin calcium-alkylether in the API is used as the reference marker or reference standard.
- the present invention provides the compound of formula I-ether of the following structure,
- R is a carboxyl protecting group that is not methyl ester and R 1 is a C 1- C 8 linear or branched alkyl.
- the invention provides the compound of formula I-ether wherein R is a carboxyl protecting group that is not methyl ester and R 1 is a C 2- C 8 linear or branched alkyl.
- the present invention provides an isolated compound of formula I-ether, wherein R is a carboxyl protecting group, and R 1 is a C 2- C 8 linear or branched alkyl. In a preferred aspect of the invention, R 1 is methyl.
- R is tert-butyl carboxyl and R 1 is methyl
- the compound of formula I-ether corresponds to TB-21 -methylether of the structure
- the present invention provides a process for preparing the isolated compound of formula I-ether, wherein R is a carboxyl protecting group and Rl is a C 1 -Cg linear or branched alkyl.
- the present invention provides the compound of formula II-ether, of the following structure,
- R is a carboxyl protecting group and R 1 is a C 1- C 8 linear or branched alkyl.
- the invention provides the compound of formula I-ether wherein R is a carboxyl protecting group and R 1 is a C 2- C 8 linear or branched alkyl.
- R is tert-butyl carboxyl and R 1 is methyl
- the compound of formula II-ether corresponds to TBRE-methylether of the structure, TBRE-methylether
- the present invention provides a process for preparing the compound of formula II-ether, wherein R is as defined above and R 1 is a C 1 -C 8 linear or branched alkyl.
- the present invention provides the compound of formula III- ether (also referred to as Rosu-alkylether) and salts thereof, with the following structure,
- R 1 is a C 1- C 8 linear or branched alkyl and M is either H or a metal cation.
- the invention provides the compound of formula Ill-ether wherein R 1 is a C 2- C 8 linear or branched alkyl and M is either H or a metal cation.
- R 1 is methyl.
- M is Ca +2 .
- M is Ca + 2 and R 1 is methyl
- the compound of formula Ill-ether corresponds to rosuvastatin calcium methyl- ether having the structure
- the present invention provides a process for preparing the isolated compound Hi-ether, wherein R 1 is a C 1 -C 8 linear or branched alkyl and M is either H or a metal cation.
- the present invention provides the compound of formula I,
- R is a carboxyl protecting group, having about 0.02% to about 1.5% area by HPLC of the compound of formula I-ether.
- the present invention provides the compound of formula ⁇
- R is a carboxyl protecting group, having about 0.02% to about 1.5% area by HPLC of the compound of formula II-ether.
- the present invention provides the compound of formula III, referred to as Rosuvastatin or Rosu,
- M is H or a metal cation, preferably Ca +2 , having about 0.02% to about 0.2% area by HPLC of formula Ill-ether (Rosu-alkylether).
- the present invention provides the use of the compound of formula I-ether, formula II-ether, and Rosu-alkylether as reference standards.
- the present invention provides a process for determining the amount of: either the compound of formula I-ether in a sample of the compound of formula I, the compound of formula II-ether in a sample of the compound of formula II, or Rosu-alkylether in a sample of Rosu comprising: a) measuring by HPLC or TLC the area under a peak corresponding to the compound of formula I-ether, formula II-ether, or Rosu-alkylether, respectively, in a reference standard comprising a known amount of the compound of formula I-ether, formula II-ether, or Rosu-alkylether, respectively; b) measuring by HPLC or TLC the area under a peak corresponding to the compound of formula I-ether, formula II-ether, or Rosu-alkylether, respectively, in a sample comprising the compound of formula I and formula I-ether, or the compound of formula II and formula II-ether, or Rosu and Rosu-alkylether, respectively; and c) determining the amount of the compound of formula I-ether
- the present invention provides the use of the compound of formula I-ether, formula Il-ether, and Rosu-alkylether as reference markers.
- the present invention provides a process for determining the presence of: either the compound of formula I-ether in a sample of the compound of formula I, the compound of formula II-ether in a sample of the compound of formula II, or Rosu-alkylether in a sample of Rosu comprising: a) determining by HPLC or TLC the retention time corresponding to the compound of formula I-ether, formula II-ether, or Rosu-alkylether, respectively, in a reference marker comprising the compound of formula I- ether, formula II-ether, or Rosu-alkylether, respectively; b) determining by HPLC or TLC the retention time corresponding to the compound of formula I-ether, formula II-ether, or Rosu-alkylether, respectively, in a sample comprising the compound of formula I and formula I-ether, or the compound of formula II and formula II-ether, or Rosu and Rosu-alkylether, respectively; and c) determining the presence of the compound of formula I-ether, formula II- ether, or
- the present invention provides an HPLC methodology that includes the steps of: combining a sample of either the compound of formula I, formula II, or Rosu with a mixture of acetonitrile and water at a ratio of 1 :1 to obtain a solution; injecting the solution into a 100 X 4.6 mm BDS Hypersil C-18 (or similar) column, which is maintained at a temperature of about 25°C; gradually eluting the sample from the column using a mixture of buffer : acetonitrile at a ratio of 3:2 by volume, and acetonitrile and a mixture of buffer: acetonitrile: ethanol at a ratio of 2:9:9 as an eluent; and measuring the amount of either the compound of formula I- ether, formula II-ether, or Rosu-alkylether, respectively, in the relevant sample with a UV detector, preferably at a 243 nm wavelength.
- the present invention provides a process for preparing the compound of formula I,
- the present invention provides a process for preparing Rosu and salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-ether by preparing the compound of formula I according to the process described above and converting it to Rosu.
- the present invention provide a process for reducing the level of the compound of formula II-ether in a sample of the compound of formula II by a process of crystallization comprising the steps of: combining crude compound of formula II with an organic solvent selected from the group consisting of aromatic hydrocarbons, C 1 -C 5 alcohols, esters, ketones, ethers, C 5 -C 8 linear or branched hydrocarbons, nitriles, mixtures thereof, and mixtures thereof with water, to obtain a reaction mixture; heating the reaction mixture at a temperature of about 25°C to about 11O 0 C to obtain a solution; cooling the solution to a temperature of about -1O 0 C to about 2O 0 C to induce precipitation of the compound of formula II; and recovering the compound of formula II.
- the present invention provides a process for preparing the compound of formula II having about 0.2 % to about 0.02 % area by HPLC of the compound of formula II-ether by preparing the compound of formula II according to the process described above.
- the present invention provides a process for preparing Rosu and salts thereof having about 0.02 % to about 0.2 % area by HPLC by preparing the compound of formula II according to the process described above and converting it to Rosu.
- the present invention provides a process for preparing Rosu having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether, comprising: a) obtaining one or more samples of one or more batches of the compound of formula I; b) measuring the level of the compound of formula I-ether in each of the samples; c) selecting a batch of the compound of formula I having a level of formula I- ether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare Rosu.
- the present invention provides a process for preparing Rosu having about 0.02% to about 0.2% area by HPLC Rosu-alkylether, comprising: a) obtaining one or more samples of one or more batches of the compound of formula II; b) measuring the level of the compound of formula II-ether in each of the samples; c) selecting a batch of the compound of formula II having a level of formula II- ether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare Rosu.
- the present invention provides a process for preparing a pharmaceutical formulation comprising Rosu having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether, comprising: a) obtaining one or more samples of one or more batches of Rosu; b) measuring the level of the compound of Rosu-alkylether in each of the samples; c) selecting a batch of Rosu having a level of Rosu-alkylether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare a formulation comprising Rosu.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising Rosu or salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether and at least one pharmaceutically acceptable excipient.
- the present invention provides a process for preparing a pharmaceutical composition comprising combining Rosu or salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether with at least one pharmaceutically acceptable excipient.
- the present invention provides rosuvastatin and salts thereof having a low level of impurities, particularly the alklyether impurity of rosuvastatin, and a process for the preparation thereof.
- the process of the invention allows the preparation of rosuvastatin having a low level of impurities by controlling the level of process impurities arising during the synthesis process.
- the purity of the reaction product i.e., the API
- HPLC or TLC analysis is analyzed by HPLC or TLC analysis.
- the present invention provides a compound of formula I-ether, having the structure
- R is a carboxyl protecting group that is not methyl ester and R 1 is a C 1- C 8 linear or branched alkyl.
- the carboxyl protecting group in the structures within the present application may be any suitable carboxyl protecting group, especially esters, amides, or hydrazides. More preferably, the carboxyl protecting group is an ester, and most preferably is tert-butylester in the structures in the present invention.
- Formula I-ether is an impurity formed during the conversion of the intermediate compound IV
- R is a carboxyl protecting group
- the level of formula I-ether can reach as high as about 20 % area by HPLC during the conversion of intermediate compound IV to the compound of formula I.
- the presence of this impurity is problematic because the impurity participates in the remaining steps of the synthesis of Rosuvastatin, leading to other impurities, and eventually, to contaminated Rosuvastatin.
- the process of the invention controls the level of formula I-ether formed, and provides a method of purifying the intermediate compound of formula II. The invention thus allows the preparation of a final product, Rosuvastatin containing a low level of Rosu-alkylether.
- the invention comprises a process of controlling the level of formula I-ether formed during the synthesis of formula I comprising the steps of: a) combining the compound of formula IV with a C 1 -C 5 alcohol to obtain a solution; b) cooling the solution at a temperature of about -1O 0 C to about 3O 0 C; c) combining the solution of step b) with a solution of methanesulfonic acid in a mixture of a C 1 -C 5 alcohol : water having a ratio of about 6 to about 30 (v/v) to obtain a reaction mixture; and d) heating the reaction mixture at a maximum temperature of about 35 0 C to obtain the compound of formula I having a controlled level of the impurity formula I-ether.
- Suitable C 1 -C 5 alcohols include methanol, ethanol, propanol, isopropanol, butanol, and amyl alcohol. Preferred alcohols include methanol, ethanol, and isopropanol.
- Performing the reaction under dilution conditions provides control over the amount of formula I-ether that is formed.
- the solution formed in step a) contains about 13 to about 19 volumes OfC 1- C 5 alcohol per gram of the compound of formula IV, and about 0.5 to about 1 volume of water per gram of formula IV.
- the solution is preferably cooled to a temperature of about O 0 C to about 2O 0 C in step b).
- the ratio of the C 1 -C 5 alcohol and water mixture in step c) is about 20.6 (v/v).
- the solution of step b) may be combined with the solution of methanesulfonic in one portion or in sequential portions, such as in a drop-wise manner.
- the solution of methanesulfonic acid in alcohol and water is added drop-wise to the solution of step b) to obtain the reaction mixture.
- the reaction mixture is preferably formed over a period of about 0.5 hour to about 5 hours, and more preferably over a period of one hour.
- the temperature is preferably maintained at about -1O 0 C to about 3O 0 C while forming the reaction mixture.
- the reaction mixture is then heated to a temperature of no more than 35°C, preferably, to about 2O 0 C to about 35°C. Controlling the temperature while forming the reaction mixture and during heating of the reaction mixture provides control over the amount of formula I-ether that is formed as a by-product of the reaction.
- the reaction mixture preferably is heated at a temperature of about 3O 0 C for about 2 to about 10 hours prior to recovering the compound of formula I.
- the compound of formula I can be recovered from the reaction mixture by adding Brine to the reaction mixture at about room temperature, extracting the reaction mixture with an organic solvent, preferably cold toluene, and washing the reaction mixture with a saturated solution OfNaHCO 3 and with Brine. The organic phase is then dried and concentrated under vacuum.
- an organic solvent preferably cold toluene
- the compound of formula prepared as described above contains about 0.02% to about 1.5% area by HPLC of the compound of formula I-ether.
- the present invention further provides a process for preparing rosuvastatin and salts thereof containing about 0.02% to about 0.2% area by HPLC Rosu-alkylether comprising preparing the compound of formula I as described above, and converting it to rosuvastatin or salts thereof.
- the present invention also provides an isolated compound of formula I-ether, wherein R is a carboxyl protecting group, and R 1 is a C 1 -C 8 linear or branched alkyl.
- R is tert-butyl carboxyl
- R 1 is methyl
- the compound of formula I-ether corresponds to TB-21-methylether of the structure
- TB21-methylether may be characterized by data selected from: an H-NMR (CDCl 3 , 300 MHz) spectrum having peaks at about 1.32, 1.50, 2.43-2.50, 2.71-2.84, 3.40, 4.07, 6.53, 3.61, 6.21 (J Hz 16.5), 7.14, 7.62 and 7.64 ppm; and a 13 C-NMR (CDCl 3 , 75 MHz) spectrum having peaks at about: 21.84, 28.06, 32.32, 33.09, 40.09, 42.46, 45.68, 57.35, 74.38, 80.90, 115.55 (J Hz 22), 119.07, 132.07 (J R2 8), 133.57, 133.77 (J Hz 4), 137.48, 157.95, 163.73 (J Hz 251), 164.94, 170.20, 175.39, and 197.06 ppm.
- the present invention also provides a process for isolating the compound of formula I-ether from a sample containing formula I and the formula I-ether by flash chromatography.
- the compound of formula I-ether is isolated with a gradient eluent comprising a mixture of heptane and ethylacetate.
- the isolation of TB21-methylether is exemplified in example 1.
- the compound of formula I may be used to prepare rosuvastatin by a process described in co-pending US Application No. (Attorney Docket No. 1662/85704).
- Rosu-Ca +2 can be obtained by the process described in co-pending US Application No. (Attorney Docket No. 1662/85704) by combining the compound of formula II with a mixture of a C 1 -C 6 alcohol and water to obtain a reaction mixture, and adding a base such as alkali hydroxide to the reaction mixture, preferably portion- wise, to give Rosu-Na 2+ in situ. Rosu-sodium is then converted to Rosu-Ca 2+ by addition of CaCl 2 . Rosu-Ca +2 may alternatively be prepared by any other process known to one skilled in the art. hi the process of converting the compound of formula I into the compound of formula II and Rosu, the impurity of formula I-ether is also converted into the respective impurities of formula II and Rosu, namely formula II-ether and Rosu- alklyether.
- the present invention provides the compound of formula II-ether, having the structure:
- R is a carboxyl protecting group, and R 1 is a C 1 -C 8 linear or branched alkyl; preferably R 1 is methyl.
- R is tert-butyl carboxyl and R 1 is methyl, thus, the compound of formula II-ether corresponds to TBRE-methylether having the strucutre,
- TBRE-methylether may be characterized by data selected from: an 1 H-NMR (CDCl 3 , 300 MHz) spectrum having peaks at about 1.28, 1.45, 2.34, 2.40, 2.58, 2.63, 3.34, 3.38, 3.53, 3.60, 4.41, 5.5, 6.62 (J Hz 16.5), 7.10, 7.64 and 7.66 ppm; an 13 C- NMR (CDCl 3 , 75 MHz) spectrum having peaks at about: 21.74, 28.14, 32.14, 33.19, 39.95, 42.25, 42.5, 57.0, 71, 81.12, 115.0 (J Hz 21.7), 122.58, 132.26, 134.63, 139.61, 140.13, 157.34, 163.32 (J Hz 247.5), 163.50, 174.93 and 174.98 ppm; and a Mass spectra having peaks at: MH+ (ES+): 552.
- the present invention also provides the compound of formula II containing about 0.02% to about 1.5% area by HPLC of the compound of formula II-ether and a process for the preparation thereof by crystallization.
- the process comprises combining crude compound of formula II with an organic solvent selected from the group consisting of aromatic hydrocarbons, C 1 -C 5 alcohols, esters, ketones, ethers, C 5 - C 8 linear or branched hydrocarbons, nitriles, mixtures thereof and mixtures thereof with water, to obtain a mixture, heating the mixture at a temperature of about 25°C to about 11O 0 C to obtain a solution, cooling the solution to a temperature of about -1O 0 C to about 2O 0 C to induce precipitation of the compound of formula II, and recovering the compound of formula II.
- an organic solvent selected from the group consisting of aromatic hydrocarbons, C 1 -C 5 alcohols, esters, ketones, ethers, C 5 - C 8 linear or branched hydrocarbons, nitriles, mixtures
- Crude compound of formula II used in the process of the invention may have an assay of about 45 % to about 77 % area by HPLC.
- the compound of formula II obtained by the above process typically has an assay of about 80% to about 95% area by HPLC.
- Aromatic hydrocarbons suitable for use as an organic solvent include toluene and benzene.
- Toluene is a preferred aromatic hydrocarbon.
- Suitable ketones are C 3 - C 8 ketones, and acetone is a preferred ketone.
- Preferred esters include ethylacetate (referred to as EtOAc) and methylacetate.
- EtOAc ethylacetate
- the ether is either tetrahydrofuran or methyl-tertbutylether (referred to as THF and MTBE, respectively).
- Preferred C 5 -C 8 linear or branched hydrocarbons include heptane and hexane.
- the nitrile is acetonitrile (referred to as ACN).
- the mixture of crude formula II is preferably heated at a temperature of about 4O 0 C to about 90 0 C to obtain a solution.
- the solution can be seeded prior to cooling, and is preferably seeded and maintained at a temperature of about 20 0 C to about 6O 0 C for about one hour prior to cooling.
- the solution is cooled to a temperature of about O 0 C to about 5°C. More preferably, the solution is cooled gradually to a temperature of about 40 0 C to about 70 0 C to obtain a suspension, and then the suspension is further cooled to a temperature of about 0 0 C to about 1O 0 C, over a period of about 1 to about 20 hours, to obtain a precipitate of the compound of formula II.
- the suspension is preferably maintained for a period of about 1 hour to about 24 hours, more preferably over night, to obtain a precipitate of the compound of formula II.
- the precipitate of the compound of formula II can be recovered by means commonly used in the art, such as by filtering and washing with toluene, preferably cold toluene, and drying in a vacuum oven.
- the present invention further provides a process for preparing rosuvastatin and salts thereof, containing about 0.02% to about 0.2% area by HPLC Rosu-alkylether comprising preparing the compound of formula II as described above, and converting it to rosuvastatin or salts thereof.
- the present invention further provides the compound of formula Ill-ether (Rosu-alkylether), having the structure:
- R 1 is a C 1 -C 8 linear or branched alkyl, preferably methyl, and M is either H or a metal cation, preferably Ca +2 .
- M is Ca + 2 and R 1 is methyl, thus, the compound of formula II- ether corresponds to rosuvastatin calcium methyl-ether having the strucutre,
- Rosu calcium-methylether may be characterized by data selected from: an 1 H- NMR (DMSOd 6 , 600 MHz) spectrum having peaks at about 1.21, 1.40, 1.70, 2.01, 2.30, 3.13, 3.20, 3.43, 3.45, 3.57, 3.60, 3.74, 4.16, 5.52, 6.51 (J Hz 16.2), 7.28 and 7.71 ppm; and a Mass spectra having peaks at: MH+ (ES+): 496.
- 1 H- NMR DMSOd 6 , 600 MHz
- the present invention also provides rosuvastatin or salts thereof containing about 0.02% to about 0.2% area by HPLC of Rosu-alkylether.
- the present invention provides a process of using the compounds of formula I- ether, formula II-ether, and Rosu-alkylether as reference standards.
- the compounds are useful for determining the amount of either: the compound of formula I-ether in a sample of the compound of formula I, the compound of formula II-ether in a sample of the compound of formula II, or Rosu- alkylether in a sample of Rosu.
- the process of using the compounds as reference standards comprises:
- the present invention also a process of using the compounds of formula I- ether, formula II-ether, and Rosu-alkylether as reference markers.
- the compounds are useful in determining the presence of either: the compound of formula I-ether in a sample of the compound of formula I, the compound of formula II-ether in a sample of the compound of formula II, or Rosu- alkylether in a sample of Rosu.
- the process of using the compounds as reference markers comprises:
- the present invention provides an HPLC methodology that includes the steps of: combining a sample of either the compound of formula I, formula II or Rosu with a mixture of acetonitrile and water at a ratio of 1 : 1 to obtain a solution; injecting the solution into a 100 X 4.6 mm BDS Hypersil C- 18 (or similar) column, which is maintained at a temperature of about 25°C; gradually eluting the sample from the column using a mixture of buffer : acetonitrile at a ratio of 3:2 by volume, and acetonitrile and a mixture of buffer: acetonitrile: ethanol at a ratio of 2:9:9 as an eluent; and measuring the amount of the compound of formula I-ether, formula II- ether or Rosu-alkylether, respectively, in the relevant sample with a UV detector, preferably at a 243 nm wavelength.
- the buffer contains a mixture of an aqueous solution of glacial acetic acid having a concentration of about 0.05%.
- the eluent used is a mixture of eluent A, eluent B, and eluent C, preferably wherein the ratio of the three eluents varies over time, i.e. a gradient eluent.
- the eluent may contain 100% of eluent A, 0% of eluent B and 0% of eluent C.
- the eluent may contain 60% of eluent A, 40% of eluent B and 0% of eluent C.
- the eluent may contain 0% of eluent A, 0% of eluent B and 100% of eluent C.
- the eluent may contain 0% of eluent A, 0% of eluent B and 100% of eluent C.
- the process of the invention for preparing Rosu having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether comprises: a) obtaim ' ng one or more samples of one or more batches of the compound of formula I; b) measuring the level of the compound of formula I-ether in each of the samples; c) selecting a batch of the compound of formula I having a level of formula I- ether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare Rosu.
- the level of the compound of formula I-ether measured in step b) is higher than about 0.02 % to about 0.2 % area by HPLC, it may be reduced by converting the compound of formula I to the compound of formula II, according to the process known in the art, followed by reducing the level of the impurity of formula II-ether (which was obtained during conversion) according to the crystallization process described above.
- the present invention also provides a process for preparing Rosu having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether, comprising: a) obtaining one or more samples of one or more batches of the compound of formula II; b) measuring the level of the compound of formula II-ether in each of the samples; c) selecting a batch of the compound of formula II having a level of formula II- ether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare Rosu.
- step b) If the level of the compound of formula II-ether measured in step b) is higher than about 0.02 % to about 0.2 % area by HPLC, it may be reduced according to the crystallization process described above.
- the present invention further provides a process for preparing a pharmaceutical formulation comprising Rosu having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether, comprising: a) obtaining one or more samples of one or more batches of Rosu; b) measuring the level of the compound of Rosu-alkylether in each of the samples; c) selecting a batch of Rosu having a level of Rosu-alkylether of about 0.02 % to about 0.2 % area by HPLC, based on the measurement of the samples from the batches; and d) using the selected batch to prepare a formulation comprising Rosu.
- the present invention also provides a process for preparing a pharmaceutical composition comprising combining Rosu or salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether with at least one pharmaceutically acceptable excipient.
- Crude Formula II (22.41 g, assay 76.7%) was stirred in toluene (56 mL). The mixture was heated to about 90°C until complete dissolution. The solution was then cooled to about 25°C, seeded at this temperature and kept for 1 hour at 25°C. A suspension formed, and was cooled to about 0°C over 2 hours and stirred at this temperature overnight to obtain a precipitate. The precipitate obtained was filtered, washed with cold toluene (10 mL) and dried at 50 0 C in a vacuum oven to get 14.23 g (assay 94.6) of formula II crystals.
- the compound of formula II (1.75 g, containing 0.20% area by HPLC of formula II-methylther) was combined with a mixture of ACN (4.5 ml) and water (3 ml) and heated until complete dissolution. A two layered system was observed, and the mixture was allowed to cool to room temperature, followed by cooling in an ice bath for 18 hrs. The solid was then filtered under reduced pressure, washed, and dried at 50°C under reduced pressure for 18 hrs to get 1.26 g of formula II containing 0.07% area by HPLC of formula II-ether.
- the compound of formula IV (65.61 g, 52.3 % assay) was dissolved in MeOH (650 ml, 10 vol) in a 2 L reactor and cooled to about 1O 0 C.
- the resulting mixture was heated to about 3O 0 C and stirred at this temperature for 10 hours.
- Example 5 Comparative example: a repetition of Example 2, step b of WO 03/097614
- the compound of formula IV (3 g, 71.9 % assay) was dissolved in MeOH (7.5 ml) and heated to about 34 0 C in a flask. A solution of methanesulphonic acid (0.19) in MeOH (7.5 ml) and H 2 O (3 ml) was added to the flask. The resulting mixture was stirred at 34 0 C for 7.5 hrs.
- Active carbon was added to the aqueous phase and the aqueous phase was stirred at 25 ⁇ 5°C for 30 minutes.
- the aqueous phase was filtered under reduced pressure with Sinter and Hyflo to eliminate the active carbon present.
- the aqueous phase was then concentrated under reduced pressure at 40 0 C to half its volume.
- Water (50 mL) was added to the aqueous phase, forming a solution.
- the solution was heated to 40°C.
- CaCl 2 (4.13 g) was added dropwise to this solution over 30-90 minutes at 38-45°C.
- the solution was then cooled to 25 ⁇ 5°C, stirred at 25 ⁇ 5°C for 1 hour, filtered, and washed with water (4 x 20 ml), yielding a powdery compound (16.7 g dry, 90%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007509753A JP4713574B2 (ja) | 2005-02-22 | 2006-02-22 | ロスバスタチンアルキルエーテルを含まないロスバスタチンおよびその塩およびそれらを製造する方法 |
| ES06735971T ES2389565T3 (es) | 2005-02-22 | 2006-02-22 | Rosuvastatina y sales de la misma carentes de alquiléter de rosuvatatina y un procedimiento para la preparación de las mismas |
| PL06735971T PL1851206T3 (pl) | 2005-02-22 | 2006-02-22 | Rozuwastatyna i jej wolne od alkilenowych eterów sole oraz sposób ich wytwarzania |
| EP06735971A EP1851206B1 (en) | 2005-02-22 | 2006-02-22 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| CA2591439A CA2591439C (en) | 2005-02-22 | 2006-02-22 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| IL184035A IL184035A (en) | 2005-02-22 | 2007-06-19 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
Applications Claiming Priority (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65558005P | 2005-02-22 | 2005-02-22 | |
| US60/655,580 | 2005-02-22 | ||
| US67638805P | 2005-04-28 | 2005-04-28 | |
| US60/676,388 | 2005-04-28 | ||
| US72349105P | 2005-10-03 | 2005-10-03 | |
| US60/723,491 | 2005-10-03 | ||
| US72387505P | 2005-10-04 | 2005-10-04 | |
| US60/723,875 | 2005-10-04 | ||
| US73297905P | 2005-11-02 | 2005-11-02 | |
| US60/732,979 | 2005-11-02 | ||
| US75107905P | 2005-12-15 | 2005-12-15 | |
| US60/751,079 | 2005-12-15 | ||
| US76050606P | 2006-01-19 | 2006-01-19 | |
| US60/760,506 | 2006-01-19 | ||
| US76234806P | 2006-01-25 | 2006-01-25 | |
| US60/762,348 | 2006-01-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006091770A2 true WO2006091770A2 (en) | 2006-08-31 |
| WO2006091770A3 WO2006091770A3 (en) | 2007-05-31 |
Family
ID=38832611
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2006/006520 WO2006091771A2 (en) | 2005-02-22 | 2006-02-22 | Preparation of rosuvastatin |
| PCT/US2006/006519 WO2006091770A2 (en) | 2005-02-22 | 2006-02-22 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2006/006520 WO2006091771A2 (en) | 2005-02-22 | 2006-02-22 | Preparation of rosuvastatin |
Country Status (11)
| Country | Link |
|---|---|
| US (3) | US7612203B2 (ja) |
| EP (2) | EP1737829A2 (ja) |
| JP (2) | JP4713574B2 (ja) |
| KR (2) | KR101020024B1 (ja) |
| CA (4) | CA2683975A1 (ja) |
| ES (1) | ES2389565T3 (ja) |
| IL (2) | IL184035A (ja) |
| MX (1) | MX2007010138A (ja) |
| PL (1) | PL1851206T3 (ja) |
| TW (2) | TWI345562B (ja) |
| WO (2) | WO2006091771A2 (ja) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008036286A1 (en) * | 2006-09-18 | 2008-03-27 | Teva Pharmaceutical Industries Ltd. | Crystalline rosuvastatin calcium |
| US7612203B2 (en) | 2005-02-22 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| EP2646420A1 (en) * | 2010-11-29 | 2013-10-09 | Egis Gyógyszergyár Nyilvánosan M Köd Részvénytársaság | Method for the preparation of high-purity pharmaceutical intermediates |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070179166A1 (en) * | 2003-12-24 | 2007-08-02 | Valerie Niddam-Hildesheim | Process for preparation of statins with high syn to anti ratio |
| WO2008053334A2 (en) * | 2006-10-31 | 2008-05-08 | Aurobindo Pharma Limited | An improved process for preparing rosuvastatin calcium |
| WO2008096257A1 (en) * | 2007-02-08 | 2008-08-14 | Aurobindo Pharma Limited | An improved process for preparation of rosuvastatin calcium |
| PL2172471T3 (pl) | 2007-04-18 | 2013-08-30 | Teva Pharma | Sposób otrzymywania produktów pośrednich inhibitorów reduktazy HMG-CoA |
| EP2178890A1 (en) | 2007-07-12 | 2010-04-28 | Teva Pharmaceutical Industries Ltd. | Purification of rosuvastatin intermediate by thin film evaporation and chemical method |
| EP2223909A1 (en) | 2007-08-28 | 2010-09-01 | Ratiopharm GmbH | Process for preparing pentanoic diacid derivatives |
| WO2009143776A1 (zh) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | 瑞舒伐他汀钙盐的制备方法及其中间体 |
| CN101735272B (zh) * | 2009-12-11 | 2012-10-31 | 重庆博腾制药科技股份有限公司 | 瑞舒伐他汀钙中间体的制备方法 |
| CN102212082B (zh) * | 2010-04-05 | 2015-03-04 | 重庆博腾制药科技股份有限公司 | 瑞舒伐他汀钙中间体及制备方法 |
| US20110313131A1 (en) * | 2010-06-21 | 2011-12-22 | Christelle Carl | Reversed phase hplc purification of a glp-1 analogue |
| EP3666778B1 (en) | 2010-08-10 | 2021-11-10 | Melinta Therapeutics, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| US9012491B2 (en) | 2011-08-31 | 2015-04-21 | Rempex Pharmaceuticals, Inc. | Heterocyclic boronic acid ester derivatives and therapeutic uses thereof |
| US9156858B2 (en) | 2012-05-23 | 2015-10-13 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US10561675B2 (en) | 2012-06-06 | 2020-02-18 | Rempex Pharmaceuticals, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| CA2894891A1 (en) | 2013-01-04 | 2014-07-10 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US9101638B2 (en) | 2013-01-04 | 2015-08-11 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| CN104981239B (zh) | 2013-01-04 | 2019-01-04 | 莱姆派克斯制药公司 | 硼酸衍生物及其治疗用途 |
| US9241947B2 (en) | 2013-01-04 | 2016-01-26 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US9518028B2 (en) | 2013-07-16 | 2016-12-13 | Suven Life Sciences Limited | Process for the preparation of Rosuvastatin calcium and preparation of its novel intermediates |
| FI3604316T3 (fi) | 2014-05-05 | 2024-02-29 | Melinta Therapeutics Inc | Boronaattisuolojen synteesi |
| EP3139930A4 (en) | 2014-05-05 | 2018-01-17 | Rempex Pharmaceuticals, Inc. | Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof |
| BR112016026291A2 (pt) | 2014-05-19 | 2017-08-15 | Rempex Pharmaceuticals Inc | Derivados do ácido borônico e usos terapêuticos dos mesmos |
| CA2952968A1 (en) | 2014-07-01 | 2016-01-07 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US10662205B2 (en) | 2014-11-18 | 2020-05-26 | Qpex Biopharma, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| WO2016149393A1 (en) | 2015-03-17 | 2016-09-22 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| KR101710976B1 (ko) * | 2015-04-08 | 2017-02-28 | 임광민 | 키랄 화합물의 제조방법 및 이를 이용한 HMG-CoA 환원저해제의 제조방법 |
| KR20160126700A (ko) | 2015-04-24 | 2016-11-02 | 미래파인켐 주식회사 | 스타틴의 중간체, 이의 제조방법 및 이를 이용한 로수바스타틴의 제조방법 |
| ES2894251T3 (es) | 2016-06-30 | 2022-02-14 | Qpex Biopharma Inc | Derivados de ácido borónico y usos terapéuticos de los mismos |
| CN111212843A (zh) | 2017-10-11 | 2020-05-29 | Qpex生物制药有限公司 | 硼酸衍生物及其合成 |
| CN112424209A (zh) | 2018-04-20 | 2021-02-26 | Qpex生物制药有限公司 | 硼酸衍生物及其治疗用途 |
| CN108845058A (zh) * | 2018-08-13 | 2018-11-20 | 江苏悦兴医药技术有限公司 | 一种瑞舒伐他汀钙起始物料的高效液相色谱检测方法 |
| CN115677768A (zh) * | 2022-09-27 | 2023-02-03 | 宿迁阿尔法科技有限公司 | 一种(3r)-叔丁基二甲硅氧基-5-氧代-6-三苯基膦烯己酸甲酯的合成方法 |
Family Cites Families (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| MX7065E (es) * | 1980-06-06 | 1987-04-10 | Sankyo Co | Un procedimiento microbiologico para preparar derivados de ml-236b |
| US5354772A (en) * | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
| US4739073A (en) * | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
| NO177005C (no) * | 1988-01-20 | 1995-07-05 | Bayer Ag | Analogifremgangsmåte for fremstilling av substituerte pyridiner, samt mellomprodukter til bruk ved fremstillingen |
| US5189164A (en) * | 1989-05-22 | 1993-02-23 | Sandoz Ltd. | Processes for the synthesis of syn-(E)-3,5-dihydroxy-7-substituted hept-6-enoic and heptanoic acids and derivatives and intermediates thereof |
| JPH03223231A (ja) * | 1990-01-29 | 1991-10-02 | Daiso Co Ltd | 蓚酸モノエステル誘導体の製造法 |
| US5177080A (en) * | 1990-12-14 | 1993-01-05 | Bayer Aktiengesellschaft | Substituted pyridyl-dihydroxy-heptenoic acid and its salts |
| US5202029A (en) * | 1991-03-13 | 1993-04-13 | Caron Kabushiki Kaisha | Process for purification of hmg-coa reductase inhibitors |
| DE69223603T2 (de) * | 1991-06-19 | 1998-04-09 | Shionogi Seiyaku Kk | Optisch aktives zwischenprodukt und dessen herstellung |
| JP2648897B2 (ja) * | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
| GB9211796D0 (en) * | 1992-06-04 | 1992-07-15 | Ici Plc | Heterocyclic derivatives |
| US5218138A (en) * | 1992-09-02 | 1993-06-08 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Stereoselective reduction of 3-hydroxyket-1-ones to 1,3-syn-dihydroxylated compounds |
| JPH06107599A (ja) * | 1992-09-30 | 1994-04-19 | Taoka Chem Co Ltd | 芳香族ジカルボン酸モノエステル類の製造方法 |
| JP3400038B2 (ja) | 1993-10-19 | 2003-04-28 | 塩野義製薬株式会社 | ピリミジン誘導体の製造方法 |
| US5741934A (en) * | 1996-04-10 | 1998-04-21 | Sandler; Stanley R. | Preparation of primary mercaptans |
| GB9626746D0 (en) | 1996-12-23 | 1997-02-12 | Knoll Ag | Process |
| GB9812413D0 (en) * | 1998-06-10 | 1998-08-05 | Glaxo Group Ltd | Compound and its use |
| DE19841342A1 (de) * | 1998-09-10 | 2000-04-20 | Merck Patent Gmbh | Neue Reaktivsysteme aus polymerisierbaren Monomeren , die Peroxide und stabilisierten Boralkylverbindungen enthalten |
| SI20070A (sl) | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Nove soli inhibitorjev HMG-CoA reduktaze |
| GB9903472D0 (en) | 1999-02-17 | 1999-04-07 | Zeneca Ltd | Chemical process |
| GB0001621D0 (en) * | 2000-01-26 | 2000-03-15 | Astrazeneca Ab | Pharmaceutical compositions |
| GB0003305D0 (en) | 2000-02-15 | 2000-04-05 | Zeneca Ltd | Pyrimidine derivatives |
| GB0028429D0 (en) * | 2000-11-22 | 2001-01-10 | Astrazeneca Ab | Therapy |
| CZ2004337A3 (cs) | 2001-08-16 | 2005-01-12 | Teva Pharmaceutical Industries Ltd. | Způsob přípravy vápenatých solí statinů |
| KR20040026705A (ko) * | 2001-08-16 | 2004-03-31 | 테바 파마슈티컬 인더스트리즈 리미티드 | 스타틴의 칼슘 염 형태의 제조 방법 |
| SE0103509D0 (sv) | 2001-10-19 | 2001-10-19 | Astrazeneca Ab | Rosuvastatin in pre demented states |
| KR100511533B1 (ko) * | 2002-04-09 | 2005-08-31 | 임광민 | 키랄 중간체, 그의 제조방법 및 그를 이용한 HMG-CoA환원저해제의 제조방법 |
| AU2003228010A1 (en) | 2002-05-21 | 2003-12-02 | Ranbaxy Laboratories Limited | Process for the preparation of rosuvastatin |
| GB0218781D0 (en) | 2002-08-13 | 2002-09-18 | Astrazeneca Ab | Chemical process |
| SI1578733T1 (sl) | 2002-12-10 | 2011-07-29 | Ranbaxy Lab Ltd | Postopek za pridobitev rosuvastatina |
| WO2004103977A2 (en) * | 2003-05-21 | 2004-12-02 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of pyrimidine derivatives |
| GB0312896D0 (en) * | 2003-06-05 | 2003-07-09 | Astrazeneca Ab | Chemical process |
| WO2005021511A1 (en) | 2003-08-27 | 2005-03-10 | Hetero Drugs Limited | A novel process for amorphous rosuvastatin calcium |
| EP1816126A1 (en) | 2003-08-28 | 2007-08-08 | Teva Pharmaceutical Industries Limited | Process for preparation of rosuvastatin calcium |
| CA2657076A1 (en) * | 2003-08-28 | 2005-03-17 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of rosuvastatin calcium |
| CN1886383A (zh) | 2003-10-22 | 2006-12-27 | 兰贝克赛实验室有限公司 | 无定形罗苏伐他汀钙的制备方法 |
| CA2546701C (en) * | 2003-11-24 | 2010-07-27 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| WO2005056534A1 (en) | 2003-12-02 | 2005-06-23 | Teva Pharmaceutical Industries Ltd. | Reference standard for characterization of rosuvastatin |
| US20050159615A1 (en) * | 2003-12-24 | 2005-07-21 | Entire Interest. | Process for preparation of statins with high syn to anti ratio |
| US20070179166A1 (en) * | 2003-12-24 | 2007-08-02 | Valerie Niddam-Hildesheim | Process for preparation of statins with high syn to anti ratio |
| EP1709008A1 (en) | 2004-01-19 | 2006-10-11 | Ranbaxy Laboratories Limited | Salts of hmg-coa reductase inhibitors and use thereof |
| WO2006035277A2 (en) | 2004-09-27 | 2006-04-06 | Ranbaxy Laboratories Limited | Novel processes for preparing amorphous rosuvastatin calcium and a novel polymorphic form of rosuvastatin sodium |
| GB0428328D0 (en) | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| JP2008528542A (ja) | 2005-01-31 | 2008-07-31 | チバ ホールディング インコーポレーテッド | ロスバスタチンカルシウム塩の結晶形 |
| US20070037979A1 (en) | 2005-02-22 | 2007-02-15 | Valerie Niddam-Hildesheim | Preparation of rosuvastatin |
| JP4713574B2 (ja) | 2005-02-22 | 2011-06-29 | テバ ファーマシューティカル インダストリーズ リミティド | ロスバスタチンアルキルエーテルを含まないロスバスタチンおよびその塩およびそれらを製造する方法 |
| EP1863773A1 (en) | 2005-03-22 | 2007-12-12 | Unichem Laboratories Limited | Process for preparation of rosuvastatin |
| US20080161560A1 (en) | 2005-04-04 | 2008-07-03 | Pandurang Balwant Deshpande | Process for Preparation of Calcium Salt of Rosuvastatin |
| CN1872841A (zh) | 2005-06-01 | 2006-12-06 | 信谊药厂 | 瑞舒伐他汀钙及其关键中间体的制备方法 |
| US8207333B2 (en) | 2005-06-24 | 2012-06-26 | Lek Pharmaceuticals D. D. | Process for preparing pure amorphous rosuvastatin calcuim |
| WO2006136407A1 (en) | 2005-06-24 | 2006-12-28 | Lek Pharmaceuticals D.D. | Process for preparing amorphous rosuvastatin calcium free of impurities |
| GB0514078D0 (en) | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
| WO2007099561A1 (en) | 2006-02-27 | 2007-09-07 | Cadila Healthcare Limited | Process for preparing rosuvastatin calcium |
-
2006
- 2006-02-22 JP JP2007509753A patent/JP4713574B2/ja not_active Expired - Fee Related
- 2006-02-22 ES ES06735971T patent/ES2389565T3/es active Active
- 2006-02-22 CA CA002683975A patent/CA2683975A1/en not_active Abandoned
- 2006-02-22 KR KR1020077018633A patent/KR101020024B1/ko not_active IP Right Cessation
- 2006-02-22 WO PCT/US2006/006520 patent/WO2006091771A2/en active Application Filing
- 2006-02-22 MX MX2007010138A patent/MX2007010138A/es not_active Application Discontinuation
- 2006-02-22 KR KR1020077018312A patent/KR100945763B1/ko not_active IP Right Cessation
- 2006-02-22 CA CA2594017A patent/CA2594017C/en not_active Expired - Fee Related
- 2006-02-22 JP JP2007549737A patent/JP2008526781A/ja active Pending
- 2006-02-22 EP EP06735972A patent/EP1737829A2/en not_active Withdrawn
- 2006-02-22 EP EP06735971A patent/EP1851206B1/en active Active
- 2006-02-22 CA CA002680693A patent/CA2680693A1/en not_active Abandoned
- 2006-02-22 CA CA2591439A patent/CA2591439C/en not_active Expired - Fee Related
- 2006-02-22 PL PL06735971T patent/PL1851206T3/pl unknown
- 2006-02-22 US US11/360,289 patent/US7612203B2/en not_active Expired - Fee Related
- 2006-02-22 TW TW095106000A patent/TWI345562B/zh not_active IP Right Cessation
- 2006-02-22 WO PCT/US2006/006519 patent/WO2006091770A2/en active Application Filing
- 2006-02-22 TW TW095105998A patent/TWI353981B/zh not_active IP Right Cessation
- 2006-09-12 US US11/520,296 patent/US7582759B2/en not_active Expired - Fee Related
-
2007
- 2007-06-19 IL IL184035A patent/IL184035A/en not_active IP Right Cessation
- 2007-06-19 IL IL184036A patent/IL184036A0/en unknown
-
2009
- 2009-03-11 US US12/381,449 patent/US8063211B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| None |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| US7612203B2 (en) | 2005-02-22 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| US8063211B2 (en) | 2005-02-22 | 2011-11-22 | Teva Pharmaceutical Industries, Ltd. | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| WO2008036286A1 (en) * | 2006-09-18 | 2008-03-27 | Teva Pharmaceutical Industries Ltd. | Crystalline rosuvastatin calcium |
| JP2008539278A (ja) * | 2006-09-18 | 2008-11-13 | テバ ファーマシューティカル インダストリーズ リミティド | 結晶性ロスバスタチンカルシウム |
| US7994178B2 (en) | 2006-09-18 | 2011-08-09 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia |
| EP2646420A1 (en) * | 2010-11-29 | 2013-10-09 | Egis Gyógyszergyár Nyilvánosan M Köd Részvénytársaság | Method for the preparation of high-purity pharmaceutical intermediates |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1851206B1 (en) | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof | |
| EP1873148B1 (en) | Pharmaceutical compositions containing crystalline salts of 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid | |
| US9371291B2 (en) | Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof | |
| EP3372607B1 (en) | Crystalline form of btk kinase inhibitor and preparation method thereof | |
| AU762909B2 (en) | Crystalline bis((E)-7- ( 4-(4- fluorophenyl)- 6-isopropyl-2- [methyl (methylsulfonyl) amino) pyrimidin -5-yl) (3R,5S)-3, 5-dihydroxyhept -6-enoic acid]calcium salt | |
| EP1663989B1 (en) | CRYSTALLINE FORM OF BIS (E)-7- 4-(4-FLUOROPHENYL)-6-IS OPROPYL-2- METHYL(METHYLSULFONYL)AMINO PYRIMIDIN-5-YL&r sqb;(3R,5S)-3,5-DIHYDROXYHEPT-6 -ENOICACID CALCIUM SALT | |
| US11661424B2 (en) | Process for preparing BTK inhibitors | |
| EP2508514A1 (en) | Process for preparing amorphous rosuvastatin calcium free of impurities | |
| AU2017303898A1 (en) | Production method for pyrazole-amide compound | |
| WO2012073055A1 (en) | Method for the preparation of high-purity pharmaceutical intermediates | |
| CN101128437A (zh) | 不含罗苏伐他汀烷基醚的罗苏伐他汀及其盐以及制备它们的方法 | |
| WO2008093205A2 (en) | A method for the purification of rosuvastatin intermediate | |
| EP4122928A1 (en) | Solid form of pyrazine substituted nicotinamide, and preparation and use thereof | |
| GB2115809A (en) | Process for preparing 4-amino-5-dialkoxy-methylpyrimidine derivatives | |
| MXPA06004553A (en) | Process for the manufacture of the calcium salt of rosuvatatin (e)-7-`4- (4-fluorophenyl) -6-isopropyl-2-`methyl (methylsulfonyl) amino ! pyrimidin -5-yl ! (3r, 5s) -3, 5-dihydroxyhept-6-enoic acid and crystalline intermediates thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 200680005642.4 Country of ref document: CN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2006735971 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2007509753 Country of ref document: JP |
|
| ENP | Entry into the national phase |
Ref document number: 2591439 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 184035 Country of ref document: IL |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 5161/DELNP/2007 Country of ref document: IN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1020077018633 Country of ref document: KR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2007/010140 Country of ref document: MX |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |